Multiple Sclerosis (MS) is an autoimmune disease of the CNS characterized by demyelination and neurodegeneration in response to perivascular T cell and mononuclear cell infiltration. Currently FDA-approved MS disease modifying therapies are global immunosuppressants mediating non-specific inhibition of T cell activation/function and/or trafficking. These drugs generally have limited efficacy and/or are associated with serious side effects. The Miller lab has recently demonstrated an effective means of ameliorating disease in the EAE mouse model of MS via tolerance induction in autoreactive T cells induced by the intravenous infusion of 500nM carboxylated poly(lactic-co-glycolic acid) (PLG) nanoparticles coupled with or encapsulating myelin peptides (Ag-PLG). Ag-PLG nanoparticles effectively reduce disease in relapsing-remitting (RR-EAE) and chronic-progressive (C-EAE) mouse models of experimental autoimmune encephalomyelitis (EAE) by tolerizing encephalitogenic Th1/17 cells. The Ag-PLG tolerance approach is currently undergoing phase 1 testing in celiac disease patients. Additionally, there are currently no FDA-approved therapies marketed for promoting remyelination. We have recently found that digoxin, an FDA-approved cardiac glycoside (Na+/K+ ATPase), and miconazole, an FDA-approved anti-fungal agent, promote oligodendrocyte differentiation and maturation and robustly induce remyelination with negligible side effects in two non-T cell-mediated demyelination models - cuprizone and DTA-induced mouse demyelinating models. As both autoimmunity and neurodegeneration underlie MS pathogenesis, effective disease modifying therapies need to both regulate the immune system and promote restoration of neuronal function, including remyelination. Thus, we will test the hypothesis that remyelination can be more efficiently induced in mice in which underlying autoimmune responses are specifically regulated. The proposed research will examine the effects of therapy with digoxin or miconazole to promote endogenous remyelination by stimulating oligodendrocyte progenitor cells (OPCs) alone or in combination with Ag-PLG tolerance-based immunotherapy in T cell-mediated demyelinating disease. The drugs will be tested in two autoimmune-mediated mouse EAE models of relapsing-remitting and chronic-progressive MS providing the ability to test myelin repair promoting strategies in the two major clinical disease types observed in MS patients. We hypothesize that since both autoimmunity and neurodegeneration underlie MS pathogenesis, effective disease modifying therapies need to both regulate the immune system and promote restoration of neuronal function by stimulating myelin repair. These studies will combine the complimentary expertise of the Miller lab and collaborators (Drs. Popko and Tesar) in tolerance-based immunotherapy and molecular aspects of myelination, and will hopefully pave the way for future clinical studies employing this combinatorial therapeutic approach in MS patients.